Systematic Study of Steroid Drugs' Ability to Cross Biomembranes-The Possible Environmental Impact and Health Risks Associated with Exposure During Pregnancy.

Thirty-seven steroid drugs of different types were investigated in silico for their environmental and pharmacokinetic properties (partition between soil and water, bioaccumulation in aquatic organisms, ability to be absorbed from the gastrointestinal tract and to cross biological barriers-skin, blood-brain barrier and placenta) using on-line tools and novel QSAR models. The same drugs were studied by Molecular Docking in the context of their ability to interact with two enzymes-glutathione S-transferase (GST) and human N-acetyltransferase 2 (NAT2), which are involved in the placenta's protective system against harmful xenobiotics. Steroid drugs are released to the environment from households, hospitals, manufacturing plants and farms (e.

Organic Sunscreens-Is Their Placenta Permeability the Only Issue Associated with Exposure During Pregnancy? In Silico Studies of Sunscreens' Placenta Permeability and Interactions with Selected Placental Enzymes.

One of the functions of placenta is to protect the fetus against harmful xenobiotics. Protective mechanisms of placenta are based on enzymes, e.g.

Organic Sunscreens and Their Products of Degradation in Biotic and Abiotic Conditions-In Silico Studies of Drug-Likeness and Human Placental Transport.

A total of 16 organic sunscreens and over 160 products of their degradation in biotic and abiotic conditions were investigated in the context of their safety during pregnancy. Drug-likeness and the ability of the studied compounds to be absorbed from the gastrointestinal tract and cross the human placenta were predicted in silico using the SwissADME software (for drug-likeness and oral absorption) and multiple linear regression and "ARKA" models (for placenta permeability expressed as fetus-to-mother blood concentration in the state of equilibrium), with the latter outperforming the MLR models. It was established that most of the studied compounds can be absorbed from the gastrointestinal tract.

Quantitative Evaluation of Stance as a Sensitive Biomarker of Postural Ataxia Development in Preclinical SCA1 Mutation Carriers.

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6 years (SCA1 +) aged 27.8 ± 8.

Quantitative Speech Assessment in Ataxia-Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Markers.

Dysarthria is a common and debilitating symptom of many neurodegenerative diseases, including those resulting in ataxia. Changes to speech lead to significant reductions in quality of life, impacting the speaker in most daily activities. Recognition of its importance as an objective outcome measure in clinical trials for ataxia is growing.

Consistency of the results of neurophysiological examinations with clinical diagnosis formed by the referring physician in ambulatory medical care.

Purpose: Access to electroneurographic/electromyographic (ENG/EMG) examinations and the number of patients referred for electrodiagnostic (EDX) examination are increasing. We aimed to determine the accuracy of the initial clinical diagnosis made by outpatient medical care physicians who referred patients to the EMG laboratory.

Methods: We analyzed referrals and EDX results of all patients who visited EMG laboratory of the Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology in Warsaw in 2021.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia.

Immobilized Keratin HPLC Stationary Phase-A Forgotten Model of Transdermal Absorption: To What Molecular and Biological Properties Is It Relevant?

Chromatographic retention data collected on immobilized keratin (KER) or immobilized artificial membrane (IAM) stationary phases were used to predict skin permeability coefficient (log ) and bioconcentration factor (log ) of structurally unrelated compounds. Models of both properties contained, apart from chromatographic descriptors, calculated physico-chemical parameters. The log model, containing keratin-based retention factor, has slightly better statistical parameters and is in a better agreement with experimental log data than the model derived from IAM chromatography; both models are applicable primarily to non-ionized compounds.

In silico assessment of risks associated with pesticides exposure during pregnancy.

Novel Quantitative Structure-Activity Relationship (QSAR) models of compounds' placenta (PL) permeability expressed as their log FM (fetus-to-mother blood concentration) values or binary PL1/0 (crossing/non-crossing) score were generated using a number of statistical tools: Multiple Linear Regression, Boosted Trees, Principal Component Analysis and Artificial Neural Networks, on the basis of molecular descriptors calculated by Mordred software and selected using Partial Least Squares (PLS) analysis. It was established that the most important predictor of both log FM and the binary PL1/0 score is Lipinski - a binary variable reflecting the compounds' ability to satisfy the criteria of drug-likeness according to the Lipinski's "Rule of 5". The quantitative (log FM) and qualitative (PL1/0) models of PL permeability were applied to 345 pesticides from different chemical families (triazines, carbamates, pyrethroids, organochlorine, organophosphorus and miscellaneous compounds).

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response.

Affinity of Compounds for Phosphatydylcholine-Based Immobilized Artificial Membrane-A Measure of Their Bioconcentration in Aquatic Organisms.

The (bioconcentration factor) of solutes in aquatic organisms is an important parameter because many undesired chemicals enter the ecosystem and affect the wildlife. Chromatographic retention factor log obtained from immobilized artificial membrane (IAM) HPLC chromatography with buffered, aqueous mobile phases and calculated molecular descriptors obtained for a group of 120 structurally unrelated compounds were used to generate useful models of log . It was established that log obtained in the conditions described in this study is not sufficient as a sole predictor of bioconcentration.

Immobilized artificial membrane-chromatographic and computational descriptors in studies of soil-water partition of environmentally relevant compounds.

Chromatographic retention factor log k obtained from immobilized artificial membrane (IAM) HPLC with buffered, aqueous mobile phases and calculated molecular descriptors (molecular weight - log M; molar volume - V; polar surface area - PSA; total count of nitrogen and oxygen atoms -(N + O); count of freely rotable bonds - FRB; H-bond donor count - HD; H-bond acceptor count - HA; energy of the highest occupied molecular orbital - E; energy of the lowest unoccupied orbital - E; dipole moment - DM; polarizability - α) obtained for a group of 175 structurally unrelated compounds were tested in order to generate useful models of solutes' soil-water partition coefficient normalized to organic carbon log K. It was established that log k obtained in the conditions described in this study is not sufficient as a sole predictor of the soil-water partition coefficient. Simple, potentially useful models based on log k and a selection of readily available, calculated descriptors and accounting for over 88% of total variability were generated using multiple linear regression (MLR) and artificial neural networks (ANN).

C9orf72 hexanucleotide repeat expansion found in suspected spinobulbar muscular atrophy (SBMA).

Introduction: The expansion of a hexanucleotide GGGGCC repeat (G4C2) in the C9orf72 locus is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, C9orf72 expansion has also been detected in patients with a clinical manifestation of Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and ataxic disorders.

Material And Methods: A total of 1,387 patients with clinically suspected ALS, HD or spinal and bulbar muscular atrophy (SBMA) were enrolled, and the prevalence of C9orf72 expansions was estimated.

IAM Chromatographic Models of Skin Permeation.

Chromatographic retention factor log obtained from IAM HPLC chromatography with buffered aqueous mobile phases and calculated molecular descriptors (surface area-; molar volume-; polar surface area-; count of freely rotable bonds-; H-bond acceptor count-; energy of the highest occupied molecular orbital-; energy of the lowest unoccupied orbital-; and polarizability-) obtained for a group of 160 structurally unrelated compounds were tested in order to generate useful models of solutes' skin permeability coefficient log . It was established that log obtained in the conditions described in this study is not sufficient as a sole predictor of the skin permeability coefficient. Simple put, potentially useful models based on log and readily available calculated descriptors, accounting for 85 to 91% of the total variability, were generated using Multiple Linear Regression (MLR).

RP-18 TLC and Computational Descriptors of Skin Permeability of Sunscreens.

The relationships between the reversed-phase thin layer chromatographic retention parameters obtained on octadecyl-modified silica (RP-18) sorbent for mobile phases containing water and one of six water-miscible organic modifiers (acetone, methanol, acetonitrile, tetrahydrofurane, N,N-dimethylformamide, 1,4-dioxane) and skin permeability coefficients were studied for a group of 21 cosmetic raw materials, mainly organic sunscreens and preservatives. The correlations between the skin permeability coefficients log Kd calculated in silico using EpiSuite software and the RP-18 thin layer chromatographic retention parameters are mostly linear, especially for compounds of lower-to-medium lipophilicity. It was established that skin permeability coefficient models based on retention parameters collected for mobile phases containing acetone or dioxane (75% v/v), proposed for structurally unrelated cosmetic raw materials are also applicable to other actives, as shown using a test set of compounds whose in vivo log Kd data are available.

RP-18 TLC Chromatographic and Computational Study of Skin Permeability of Steroids.

The skin permeability of steroids, as investigated in this study, is important because some of these compounds are, or could, be used in preparations applied topically. Several models of skin permeability, involving thin layer chromatographic and calculated descriptors, were generated and validated using reference values obtained in silico and then tested on a group of solutes whose experimental values could be found (log ). The study established that the most applicable log model is based on RP-18 thin layer chromatographic data () and the calculated descriptors (molar volume) and (polar surface area).

Evaluation of drug-likeness and ADME properties of sunscreens and preservatives using reversed-phase thin layer chromatographic retention data and calculated descriptors.

RP-18 TLC chromatography was used to evaluate the pharmacokinetic properties (volume of distribution, V; plasma protein binding, %PPB; the ability to cross the blood-brain barrier expressed as log PS and log BB) of several cosmetic raw materials - sunscreen and preservatives. The majority of these compounds are intended for topical use on skin and their drug-likeness and the ability to cross biological barriers are undesired. The retention parameters R, S, PC and R obtained for mobile phases containing six organic modifiers (methanol, acetonitrile, THF, acetone, dioxane, DMF) were used as the sole descriptors or combined with calculated physicochemical properties (PSA, M, V) of studied compounds.

RP-18 TLC retention data and calculated physico-chemical parameters as predictors of soil-water partition and bioconcentration of organic sunscreens.

RP-18 TLC chromatography was used to evaluate the impact on the environment (mobility in soil expressed as soil-water partition coefficient, log K; bioconcentration factor in aquatic organisms, log BCF) of several cosmetic raw materials - sunscreens, preservatives and vitamins. The retention parameters R (R extrapolated to zero concentration of an organic modifier in a mobile phase), S (slope), PC (1st principal component) and R (single TLC run parameter for mobile phases containing 75% (v/v) of an organic modifier) obtained for six organic modifiers (methanol, acetonitrile, THF, acetone, dioxane, DMF) were used as the sole descriptors or combined with calculated physico-chemical properties (PSA - polar surface area; M - molecular weight; V - molar volume) of studied compounds. The chromatographic parameters considered in this study are, generally speaking, good predictors of the compounds' mobility in soil or the affinity for aquatic organisms.

Application of RP-18 TLC Retention Data to the Prediction of the Transdermal Absorption of Drugs.

Several chromatographic parameters ( and obtained from RP-18 TLC with methanol-pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; and obtained from RP-18 TLC with acetonitrile-pH 7.4 phosphate buffer 70:30 / as a mobile phase) and calculated molecular descriptors (molecular weight-; molar volume-; polar surface area-; total count of nitrogen and oxygen atoms-(); H-bond donor count-; H-bond acceptor count-; distribution coefficient-log ; total energy-; binding energy-; hydration energy-; energy of the highest occupied molecular orbital-; energy of the lowest unoccupied orbital-; electronic energy-; surface area-; octanol-water partition coefficient-log ; dipole moment-; refractivity-, polarizability-) and their combinations (/, /, /) were tested in order to generate useful models of solutes' skin permeability coefficient log .

Clinical correlates of rhinovirus infection in preschool asthma.

Background: Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group.

Objectives: To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome.

Emerging or Underestimated Silica-Based Stationary Phases in Liquid Chromatography.

Several newly synthesized or forgotten silica-based stationary phases proposed for liquid chromatography are described, including non-endcapped, short-chain alkyl phases; hydrophilic and polar-endcapped stationary phases; polar-embedded alkyl phases; long-chain alkyl phases. Stationary phases with aromatic, cyanopropyl, diol and aminopropyl functionalities are also reviewed. Stationary phases of particular interest are biomolecular materials - based on immobilized cholesterol, aminoacids, peptides, proteins or lipoproteins.

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs' dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to "traditional workflow/guidelines" by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS).

Long-term evolution of patient-reported outcome measures in spinocerebellar ataxias.

Introduction: To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6.

Methods: To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington's Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS).

Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study.

Background: Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival.

Methods: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias.